December11 ,2013’ RichardW.Hutchinson,’ DVM,PhD,’ DABT ... · HUTCHINSON 2013 12 11 TTC for Medical Devices Baltimore Dec 2013.pptx Author: Jamie DeRita Created Date: 1/9/2014

December 11th, 2013 Richard W. Hutchinson, DVM, PhD, DABT Johnson & Johnson Global Surgery Group

Agenda � Background on Risk Assessment of Medical Devices based on Analytical Characterization

� Background on TTC � Draft Standard � Practical application of the TTC approach for compounds released from devices

� Comparison of SAR packages

ISO 10993-‐ Part 1 -‐ Evalua7on & Tes7ng within a Risk Management Process � The role of this part of ISO 10993 is to serve as a framework in which to plan a biological evaluation which, as scientific knowledge advances our understanding of the basic mechanisms of tissue responses, minimizes the number and exposure of test animals by giving preference to chemical constituent testing and in vitro models, in situations where these methods yield equally relevant information to that obtained from in vivo models.

ISO 10993-‐1

FDA-‐CDRH

ISO 10993-‐17

Threshold Of Toxicological Concern �  “The Threshold of Toxicological Concern is used where there are limited or no data on the compound, but the human exposure is so low that undertaking toxicity studies is not warranted” (Renwick, 2004)

How TTC Values are calculated

Published guidance

ICH M7 Less than Life7me Exposure

ICH M7 Less than Life7me exposure

Pavia Italy April 2013

Proposed Default Threshold of Toxicological Concern Values ISO Contact Category

Limited (<24 hr)

Prolonged (24 hr to 30 days)

Permanent (>30 days)

Dura7on of treatment

< 1 month >1 -‐ 12 months

>1 -‐ 10 years

>10 years to life7me

Daily intake [μg/day]-‐ any one chemical

120 20 10 1.5

Daily intake [μg/day]-‐ total exposure to mul7ple chemicals

120 60 30 5

Hypothe7cal example �  Supplier A of Component X just went out of business, Supplier B is being considered as an alternative.

� Component X is made from pure polypropylene � Clinically it is placed in contact with open wound � Changed every week for up to 6 weeks � Both claim to be 95% pure Polypropylene, but will not disclose the other 5 %

� All other processes and additives will be identical

� What do you do?

FDA-‐CDRH

Hypothe7cal example con7nued � Compare a new plastic to a predicate plastic �  Exhaustive extraction/Exaggerated extraction conditions � Qualitative/Quantitative analytical analysis

�  LC MS, GC MS, HPLC, NMR � Report all new leachables > TTC � TTC= 20 ug per individual chemical 60 ug total �  Sort by concentration and report all above these limits

�  For this example select 15 by random # Generator Jenke 2009 list {656 leachables from medical plastics}

Hypothe7cal example con7nued CAS# Common Name IARC Class GRAS

71-‐43-‐2 Benzene Group 1: Carcinogenic to humans no

123-‐95-‐5 N-‐butyl stearate na no 112-‐80-‐1 9-‐0ctadecanoic acid na yes 111-‐46-‐6 Diethylene glycol na no 628-‐97-‐7 Ethyl palmitate na no 106-‐68-‐3 3-‐0ctanone na no 3892-‐00-‐0 2,6,10-‐Trimethylpentadecane na no 141-‐79-‐7 3-‐Methyl-‐4-‐methylene-‐hexane-‐2-‐one na no 79-‐09-‐4 Propionic acid na yes

117-‐81-‐7 Di-‐(2-‐ethylhexyl) phthalate Group 2B: Possibly carcinogenic to humans no

589-‐38-‐8 3-‐Hexanone na no 638-‐67-‐5 Tricosane na no 1565-‐94-‐2 Bisphenol A glycerolate dimethacrylate na no 5581-‐32-‐8 Bisphenol A bis(2,3-‐dihydroxypropyl)ether na no 638-‐36-‐8 2,6,10,14-‐Tetramethylhexadecane na no

ChemID

DEREK

Tox Tree

QSAR Toolbox

Hypothe7cal example 6: Mutagenicity

CAS DEREK Alert

(s)

SARAH Genetox

Alert (100% confidence of nega7ve)

Tox Tree (Cramer Class)

Tox Tree (In vitro

mutagenicity (Ames test)

alerts by ISS)

ToxTree (Genotoxic/nongenotoxi

c carcinogenici

ty by ISS)

Tox Tree (in vivo

micronucleus)

QSAR Toolbox

(Carcinogenicity)

QSAR Toolbox

(Ames, MN, CA by OASIS)

QSAR Toolbox (in

vitro mutagenicity

-‐ames)

QSAR Toolbox (in

vitro mutagenicity

-‐micronucleu

s)

QSAR Toolbox

(Oncologic)

71-‐43-‐2 Carcinogenic

ity 100 III no nega7ve no no no no no no 123-‐95-‐5 none 99 I no nega7ve no no no no yes no 112-‐80-‐1 none 100 I no nega7ve no no no no yes no

111-‐46-‐6

Bone Marrow Tox, Nephrotoxici

ty 100 I no nega7ve yes no no no yes no 628-‐97-‐7 none 99 I no nega7ve no no no no yes no 106-‐68-‐3 none 77 II no nega7ve no no no no no no 3892-‐00-‐0 alpha 2 glob 38 I no nega7ve no no no no no no

141-‐79-‐7 chromosomal damage 1 I yes

genotoxic Carcinogen yes yes no yes yes yes

79-‐09-‐4

Carcinogenicity, GI

Irrita7on 100 I no

non-‐genotoxic Carcinogen no no no no yes no

117-‐81-‐7

Teratogenicity, tes7culat toxicity 100 I no

non-‐genotoxic Carcinogen yes yes no no yes no

589-‐38-‐8 none 77 I no nega7ve no no no no no no 638-‐67-‐5 none 97 I no nega7ve no no no no no no

1565-‐94-‐2

Chromosomal Damage,

Eye irrita7on,

Skin Irrita7on,

Sensi7za7on 100 III no nega7ve yes no no no yes yes

5581-‐32-‐8 Nephrotoxici

ty 100 III no nega7ve yes no no no yes no 638-‐36-‐8 alpha 2 glob 38 I no nega7ve no no no no no no

Hypothe7cal example con7nued CAS


Tox Tree (Skin

Irrita7on)

Tox Tree (Skin

Sensi7za7on) QSAR Toolbox (eye irrita7on)

QSAR Toolbox (Sensi7za7on)

QSAR Toolbox (Skin Irrita7on)

71-‐43-‐2 III unknown no no no no 123-‐95-‐5 I irrita7ng no no no yes 112-‐80-‐1 I irrita7ng no no no no 111-‐46-‐6 I irrita7ng no no no no 628-‐97-‐7 I irrita7ng no no no yes 106-‐68-‐3 II irrita7ng no no no yes 3892-‐00-‐0 I unknown no no no no 141-‐79-‐7 I irrita7ng yes no no yes 79-‐09-‐4 I irrita7ng no no no yes 117-‐81-‐7 I no no no yes no 589-‐38-‐8 I irrita7ng no no no yes 638-‐67-‐5 I unknown no no no no

1565-‐94-‐2 III no yes no yes no 5581-‐32-‐8 III no no no no no 638-‐36-‐8 I unknown no no no no

Hypothe7cal Example Conclusions �  Known Human Carcinogen

�  only flagged by DEREK and Cramer Models {Tox Tree} �  GRAS Compounds overpredicted

�  #1: QSAR Toolbox predicted was mutagenic �  #2: DEREK, Tox Tree and QSAR Toolbox all predicted was carcinogenic

�  Skin Irritation molecules not very discriminating up to 12/15 positives-‐dose response

�  QSAR Toolbox models tended to be all positive or all negative

�  DEREK and Tox Tree modules tended to have similar results

Hypothe7cal example next steps CAS DEREK Alert (s)


71-‐43-‐2 Carcinogenicity III 123-‐95-‐5 none I 112-‐80-‐1 none I

111-‐46-‐6 Bone Marrow Tox, Nephrotoxicity I

628-‐97-‐7 none I 106-‐68-‐3 none II 3892-‐00-‐0 alpha 2 glob I 141-‐79-‐7 chromosomal damage I 79-‐09-‐4 Carcinogenicity, GI Irrita7on I

117-‐81-‐7 Teratogenicity, tes7cular toxicity I

589-‐38-‐8 none I 638-‐67-‐5 none I

1565-‐94-‐2

Chromosomal Damage, Eye irrita7on, Skin Irrita7on, Sensi7za7on III

5581-‐32-‐8 Nephrotoxicity III 638-‐36-‐8 alpha 2 glob I

� Next steps-‐ Individual risk assessment for each as per ISO 10993-‐17

� E.g. for benzene the cancer slope factor is 77.5 mg/kg/day

Conclusions � Chemical Characterization is a useful tool for Risk Assessment of Medical Devices

�  ICH M7 TTC values are the most current and widely accepted

�  ISO TC 194 has drafted an international standard describing this process

� DEREK and Tox Tree-‐Cramer Class seem to be the most useful SAR packages for medical devices.

Documents

December11 ,2013’ RichardW.Hutchinson,’ DVM,PhD,’ DABT ... · HUTCHINSON 2013 12 11 TTC for Medical Devices Baltimore Dec 2013.pptx Author: Jamie DeRita Created Date: 1/9/2014